Future of clinical trials 'in jeopardy'

[Angel]

The future of clinical trials appeared to be in jeopardy after a medicine watchdog said a drug that left six men seriously ill had an "unpredicted" response in humans.

The Medicines and Healthcare Products Regulatory Agency (MHRA) found there were no errors in the manufacture, formulation, dilution or administration of the TGN1412 drug tested on volunteers last month.

It concluded that the most likely cause of the adverse reaction seen was an "unpredicted biological action of the drug in humans".

Six men suffered multiple organ failure after being given TGN1412, which is designed to treat rheumatoid arthritis, leukaemia and multiple sclerosis.

The MHRA said it appeared that the samples of TGN1412 used had not been contaminated or "contained anything other than the correct ingredients".

It found no errors in the way the trial, conducted by research company Parexel, was carried out, or any errors in the dosage - which was 500 times weaker than that given to monkeys.

The findings raise questions over the use of animals in testing and the implications for human trials.

An expert group has now been formed to examine the issue and will report to Health Secretary Patricia Hewitt in the next three months.

The MHRA said today it would be seeking expert advice before authorising any more first-in-man trials of drugs like TGN1412.

It said in a statement: "In this case the resulting activity seen in humans was not predicted from apparently adequate pre-clinical testing.

"This is a complex scientific issue which raises important scientific and medical questions about the potential risks associated with this type of drug and how to make the transition from pre-clinical testing to trials in humans."

The German company TeGenero, which developed the drug, said it was "saddened" that the MHRA's interim findings suggested the drug had unforeseen side-effects.

"For a company dedicated to developing medicines to help millions it is devastating that such events could occur," it added.

"The preliminary findings of the investigation underline that we observed the highest standards in developing this drug and that these symptoms were both unexpected and unforeseeable.

"The announcement of a new expert commission to supervise future trials of monoclonal antibodies challenges all of us in the biotechnology industry to think again about the safest way to develop new medicines in the future."

Speaking at a press conference in central London, MHRA chief executive Professor Kent Woods said the action of TGN1412 on the immune system was at "the core" of the investigation into what went wrong.

He dismissed suggestions that there were errors in the timing of the doses given to the men.

Even if just one patient had been admitted to intensive care as a result of the trial, it "would still have been a very substantial research disaster", he added.

With hindsight, it was unfortunate that six patients were taken seriously ill but there was nothing to suggest such an extreme reaction would occur.
He added: "The secondary safety provided by the staging of treatments is not the answer to this problem."

Furthermore, the dose should have provided a safety margin.

"It's very unexpected that, with a 500-fold dilution factor, these effects in the immune system were sufficiently extreme and severe to show the clinical outcome seen in the Parexel study."

Prof Woods said the MHRA authorised some 350 phase 1 clinical trials on humans every year and the safety record of such studies was "excellent".

But Martyn Day, the solicitor representing four of the men taken ill, said he had serious concerns.

He said TGN1412 was a "novel" new drug and that had not been explained to his clients.

He added: "If it had been explained that it was so new, then there's not the slightest chance that one of them would have gone through with the test. For £2,000 Not the slightest chance."

Mr Day also expressed concern that the MHRA was "regulating itself" as it was involved in the original authorisation of the trial.

Shadow Health Secretary Andrew Lansley said an independent group needed to be set up because the "MHRA and Paul Ehrlich Institute are scrutinising their own actions".

He said he was concerned that there was a day's delay between the incident and the MHRA being notified of it.

He added: "We must know whether the inspections informing this report were undertaken by staff employed by the MHRA and the Paul Ehrlich Institute, who were also directly involved in the original clinical trial authorisation."

A fuller report rather than a summary needed to be published and knowledge of the independent and expert assessment of TGN1412 also needed to be made public, he added.

Health Minister Lord Warner insisted that clinical trials in general had "an excellent safety record" but it was vital to learn lessons for the future.

Professor Janet Darbyshire, director of the Medical Research Council clinical trials unit, added: "There is likely to be a need for novel and much more cautious approaches to testing such innovative products. Bringing together an expert group to advise on this will be very valuable."

Dr Simon Festing, executive director of the Research Defence Society, said animal testing "was like wearing a seatbelt".

He added: "It can prevent many problems, but is no guarantee of safety. We are all concerned that these severe effects apparently did not show up either in human tissue tests or animal tests. Further research will be essential."

TGN1412 is a new class of monoclonal antibody which had a stimulatory action affecting cells in the immune system.

The six men tested all had a rapid inflammatory response to the drug and were treated in Northwick Park Hospital in north-west London.

Just one patient remains at the hospital for treatment after a fifth was released today.

Also today, the Academy of Medical Sciences issued a report examining the issues surrounding the trial.

It said it would be "usual practice to administer a single dose in a single patient, who would then be observed for an appropriate period of time".

It added: "It is important to recognise that, during this crucial step of "first into man", the assessment of antibody toxicity is likely to be less precise than for conventional small molecule drugs."

The working group will be headed by Professor Gordon Duff, Professor of Molecular Medicine at Sheffield University.

Auriana Griffiths, solicitor for two of the men, said their families were "frustrated" with "inconsistent information" about the trials.

"Early on in the investigation, before the MHRA produced their results today, they had previously been told that certain animals had been tested and then in the next meeting it was different animals so at the moment there's very inconsistent information which is very frustrating for the families.

"And unfortunately, despite numerous requests to the two drug companies, TeGenero and Parexel, they have done nothing to confirm precisely what happened in the pre-human trials," she told Channel 4 News.